Protective Effect of Pyocin against Lethal Pseudomonas aeruginosa Infections in Mice

Haas, H; Sacks, T.; Saltz, Nathan J.

doi:10.1093/infdis/129.4.470

Cited by 22 publications

(21 citation statements)

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“…Particularly attractive is the potential prophylactic use of these specifically targeted bactericidal diffocins for prevention of colonization or for decolonization of asymptomatic human carriers, particularly individuals scheduled for antibiotic-mediated insults to their intestinal microbiota. Oral and parenteral R-type bacteriocins have been demonstrated to be effective prophylactics and therapeutics in animal models (6,12,21,29,30). We expect that orally administered diffocins could similarly be used to treat or prevent CDI.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, no means of prophylaxis is available except for care facility and personal hygiene, such as thorough hand washing by those persons exposed to the spores, especially hospital staff. Studies showing that phage tail-like R-type bacteriocins can be used orally and parentally to treat bacterial infections (6,12,21,29,30) have prompted us to identify similar entities specific for C. difficile for possibile use in the treatment or prevention of CDI.…”

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confidence: 99%

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Novel High-Molecular-Weight, R-Type Bacteriocins of Clostridium difficile

et al. 2012

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c Clostridium difficile causes one of the leading nosocomial infections in developed countries, and therapeutic choices are limited. Some strains of C. difficile produce phage tail-like particles upon induction of the SOS response. These particles have bactericidal activity against other C. difficile strains and can therefore be classified as bacteriocins, similar to the R-type pyocins of Pseudomonas aeruginosa. These R-type bacteriocin particles, which have been purified from different strains, each have a different C. difficile-killing spectrum, with no one bacteriocin killing all C. difficile isolates tested. We have identified the genetic locus of these "diffocins" (open reading frames 1359 to 1376) and have found them to be common among the species. The entire diffocin genetic locus of more than 20 kb was cloned and expressed in Bacillus subtilis, and this resulted in production of bactericidal particles. One of the interesting features of these particles is a very large structural protein of ϳ200 kDa, the product of gene 1374. This large protein determines the killing spectrum of the particles and is likely the receptor-binding protein. Diffocins may provide an alternate bactericidal agent to prevent or treat infections and to decolonize individuals who are asymptomatic carriers.

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Section: Discussionmentioning

confidence: 99%

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Novel High-Molecular-Weight, R-Type Bacteriocins of Clostridium difficile

et al. 2012

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“…The antibacterial efficacy of R-type pyocins in P. aeruginosa infections has previously been demonstrated in two early, cursory studies of peritonitis in mice (6,19). These studies were limited in scope, did not employ a quantitative pyocin assay to determine exact doses, and did not explore dose response, time of administration, or more than a single route of administration.…”

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confidence: 92%

“…We elected to study peritonitis in mice infected with P. aeruginosa, a target pathogen for wildtype R-2 pyocin; R-2 pyocin is lethal to many P. aeruginosa strains. Peritonitis caused by P. aeruginosa is a serious threat to children with ruptured appendices and patients undergoing continuous ambulatory peritoneal dialysis (CAPD) (1,3,13,35).The antibacterial efficacy of R-type pyocins in P. aeruginosa infections has previously been demonstrated in two early, cursory studies of peritonitis in mice (6,19). These studies were limited in scope, did not employ a quantitative pyocin assay to determine exact doses, and did not explore dose response, time of administration, or more than a single route of administration.…”

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Antibacterial Efficacy of R-Type Pyocins towards Pseudomonas aeruginosa in a Murine Peritonitis Model

Scholl

Martin

2008

Antimicrob Agents Chemother

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R-type pyocins are high-molecular-weight bacteriocins carried within the chromosomes of some bacterial species, such as Pseudomonas aeruginosa, and almost certainly evolved from lysogenic bacteriophages of the Myoviridae family. They contain no head structures and no DNA and are used as defense systems, usually against other strains of the same bacterial species. They bind with their tail fibers to targeted bacterial surface molecules and then kill by inserting a core or needle that dissipates the bacterial membrane potential. Their mechanism of action, high bactericidal potency (one pyocin particle can kill one bacterium), and focused spectrum suggest that R-type pyocins could be developed as antibacterial agents. In a lethal mouse peritonitis model, submicrogram quantities of pyocin prevent death from 90% lethal dose inocula of a pyocin-sensitive, clinical isolate of P. aeruginosa. We show here the dose response curves, treatment windows, or periods of response after infection and the several-log-unit acute reduction of bacterial load in blood and spleen samples, suggesting that R-type pyocins have several characteristics that one would expect from an effective therapeutic.Many Pseudomonas species possess the genes for one or both of the two types of high-molecular-weight pyocins, the R type and the F type (17, 28). Both are carried in the bacterial genome. The R-type pyocin locus consists of 16 open reading frames including 10 structural genes plus regulatory and chaperone genes (24, 25). Morphologically and genetically, the Rtype pyocins resemble the tails of Myoviridae bacteriophages but have no head structure and thus no nucleic acid content (9,15,16,23). They are thought to have evolved from the tail structure of a P2 bacteriophage-related ancestor; but they are not simply defective phages. There are meaningful physical and chemical stability differences, such as differences in protease and acid resistance, between pyocins and phage tails as the former have been adapted for their role as defensive bactericidal agents (14,22). However, similar to bacteriophages, pyocins bind to specific "receptors" on target bacteria and penetrate their membranes with a "core," or needle-like structure (31). In contrast to bacteriophages, pyocins have no material to inject and their penetrating core remains patent. As an immediate consequence, the bacterium is killed by dissipation of its membrane potential, a bactericidal event that can result from the binding of a single pyocin particle (8,27,31). An R-type pyocin particle can act only once; once it kills a cell, it cannot go on to kill others. Bacteriophages and R-type pyocins share common ancestry, but in contrast to bacteriophages, pyocins kill without directly causing bacterial cell lysis, a feature likely desirable for treating systemic infections (7, 33).Francois Jacob discovered and first described pyocins as high-molecular-weight bacteriocins (11). Over subsequent decades, much effort has been expended studying Pseudomonas aeruginosa pyocin morphology, structure,...

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“…The high potency of R-type pyocins suggests that they could be developed as antimicrobial agents (27), and a few studies have shown their antibacterial efficacy in mice (12,26,35). However, at the time of the early studies, broad-spectrum antibiotics were clinically effective, and there was little interest in pursuing this avenue, particularly since the limited spectra of R-type pyocins were viewed as problematic.…”

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Retargeting R-Type Pyocins To Generate Novel Bactericidal Protein Complexes

Williams

Gebhart

Martin

et al. 2008

Appl Environ Microbiol

139

206

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R-type pyocins are high-molecular-weight bacteriocins that resemble bacteriophage tail structures and are produced by some Pseudomonas aeruginosa strains. R-type pyocins kill by dissipating the bacterial membrane potential after binding. The high-potency, single-hit bactericidal kinetics of R-type pyocins suggest that they could be effective antimicrobials. However, the limited antibacterial spectra of natural R-type pyocins would ultimately compromise their clinical utility. The spectra of these protein complexes are determined in large part by their tail fibers. By replacing the pyocin tail fibers with tail fibers of Pseudomonas phage PS17, we changed the bactericidal specificity of R2 pyocin particles to a different subset of P. aeruginosa strains, including some resistant to PS17 phage. We further extended this idea by fusing parts of R2 tail fibers with parts of tail fibers from phages that infect other bacteria, including Escherichia coli and Yersinia pestis, changing the killing spectrum of pyocins from P. aeruginosa to the bacterial genus, species, or strain that serves as a host for the donor phage. The assembly of active R-type pyocins requires chaperones specific for the C-terminal portion of the tail fiber. Natural and retargeted R-type pyocins exhibit narrow bactericidal spectra and thus can be expected to cause little collateral damage to the healthy microbiotae and not to promote the horizontal spread of multidrug resistance among bacteria. Engineered R-type pyocins may offer a novel alternative to traditional antibiotics in some infections.

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Protective Effect of Pyocin against Lethal Pseudomonas aeruginosa Infections in Mice

Cited by 22 publications

References 3 publications

Novel High-Molecular-Weight, R-Type Bacteriocins of Clostridium difficile

Novel High-Molecular-Weight, R-Type Bacteriocins of Clostridium difficile

Antibacterial Efficacy of R-Type Pyocins towards Pseudomonas aeruginosa in a Murine Peritonitis Model

Retargeting R-Type Pyocins To Generate Novel Bactericidal Protein Complexes

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